Cocaine users often experience intense arousal and drug desire when encountering cues reminiscent of cocaine. This cue-induced craving state has been closely linked to relapse, and may reflect increased activity ii the mesolimbic dopamine (DA) system. In the prior funding period, we used Positron Emission Tomograph' (PET, with 0-15 water as the perfusion tracer) to demonstrate that video cues for cocaine triggered both craving and limbic (amygdalar and anterior cingulate) activation in treatment-seeking cocaine patients. Our initial hypotheses focused on this cue-induced limbic activation (GO!") as the primary culprit in relapse vulnerability However, other striking findings (e.g., hypoacrivity and gray matter hypodensity in the ventromedial orbitofronta cortex, VMOFC; neuropsychological dysfunction) from the initial funding period point to defects in our coca in patients' frontal inhibitory ("STOP! ") circuitry. These frontal regions normally modulate downstream limbin regions; frontal defects may thus help explain our patients' struggle to inhibit craving, and to resist drug use. [unreadable] [unreadable] We have thus modified our usual imaging paradigm to capture brain activity during attempted inhibition of cue-induced craving to our drug videos. This condition will be contrasted with (as a control for effort attempted increases in craving, and with our standard craving induction. Aim 1 is to determine neuroanatomica substrates for cue-induced craving, in contrast with its attempted inhibition. Results will be cross-validate between 0-15 PET (Study la), and perfusion fMRI (Study ib). Pilot data suggest attempted craving inhibition differentially activates the VMOFC. Aim 2 (Study 2) uses the paradigm and patients from Study 1 to examination neurochemical substrates: If mesolimbic DA increase is a craving substrate, modulation of DA by the GABA 1 agonist baclofen (20 mg q.i.d., vs. placebo) should blunt craving and amygdalar activation. Pilot data an encouraging. Aim 3 (Study 3) addresses neurochemical substrates directly, measuring whether cue-induced craving increases, and craving inhibition decreases, ventral striatal DA release. PET and a C-11 raclopride competition paradigm are used to infer changes in endogenous DA. As in Aim 2, baclofen (vs. placebo) pre treatment will be used to attempt blockade of cue-induced craving and the associated brain substrate. [unreadable] [unreadable] The proposed studies address both "GO!" and "STOP!" substrates: their neuroanatomy, their neurochemistry, and their interrelation. Intentionally, we use manipulations with direct clinical relevance. The revealed substrates may well be relevant for other substance, and non-substance, addictions.